The invention relates to the diagnosis and treatment of sympathetically maintained pain using sympatholytic agents which are defined herein as compounds that interfere with sympathetic function in the peripheral tissue or interfere with the action of drugs associated with sympathetic function.
Several chronic, non-malignant pain syndromes such as causalgia and reflex sympathetic dystrophy have one feature in common: blockade of the sympathetic innervation of the affected body region can lead to pain relief. The pain may result from skeletal, soft tissue, or nerve injury. Terms such as reflex sympathetic dystrophy, Sudek""s atrophy, and causalgia have all been used to refer to such patients. The term xe2x80x9csympathetically maintained painxe2x80x9d (xe2x80x9cSMPxe2x80x9d) encompasses all pain syndromes that can be relieved by sympathetic blockade.
Patients with SMP typically have both stimulus-independent (ongoing) pain and stimulus-dependent pain (hyperalgesia). Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold and/or an increase in pain to suprathreshold stimuli is observed. The decrease in pain threshold to mechanical stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.
Conventional treatments for SMP include repeated local anesthetic sympathetic blocks, intravenous regional guanethidine/reserpine blocks, surgical sympathectomy, or oral sympatholytic therapy. However, each of these treatments carries with it a degree of risk, side effects and discomfort.
One method of diagnosis of SMP is by assessment of the results of a local anesthetic blockade of the sympathetic ganglia (LABSG) that innervate the painful part. Because of the technical expertise required in the performance of the LABSG and the potential complications associated with the LASB, alternate tests for the diagnosis of SMP have been studied. For example, intravenous regional blockage (IVRB) of sympathetic function with guanethidine has been used as a means for the diagnosis and treatment of SMP.
There are several potential disadvantages to the use of LABSG and IVRB. LABSG is subject to false negative results if the local anesthetic fails to anesthetize adequately the sympathetic ganglia. The anesthetic may reach the somatic afferents in the nearby nerve roots and produce pain relief because of concurrent somatic blockade, and certain afferents may in addition course with sympathetic efferents. Certain patients tolerate poorly the application of the tourniquet required with IVRB. LABSG involves strategic localization of the needle prior to injection, and thus fluoroscopy is often needed. With IVRB, the guanethidine may escape into the systemic circulation with resultant systemic untoward effects. A series of complications have been reported with LABSG, including pneumothorax, injury to the kidney, inadvertent systemic application, spinal anesthesia, hemorrhage, etc. It is difficult to evaluate placebo responses with both LABSG and IVRB.
It would therefore be advantageous to have a method of diagnosis and treatment that does not exhibit these difficulties.
Several lines of evidence suggest that peripheral adrenergic receptors are involved in SMP. Stimulation of the peripheral but not central cut end of the sympathetic chain reproduces pain in causalgia patients after sympathectomy. Local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic blockade via intravenous administration of phentolamine, rapidly abolishes sympathetically-maintained pain and hyperalgesia. Depletion of peripheral catecholamines by regional intravenous guanethidine relieves pain and hyperalgesia. Intradermal injection of norepinephrine rekindles the pain and hyperalgesia that had been relieved in patients by sympathectomy or sympathetic block but does not cause pain or hyperalgesia in normal subjects. The non-specific xcex1-adrenergic antagonist phenoxybenzamine and the specific xcex11-adrenergic antagonist prazosin can be effective in relieving pain in patients with SMP. The beta-adrenergic antagonist propranolol has little effect on SMP.
It is therefore possible that administration of an xcex1-adrenergic blocking agent could be beneficial in the treatment of SMP patients. Therapeutic uses of the xcex1-adrenergic compounds, for example, phentolamine and clonidine, are known in the art. For example, U.S. Pat. No. 4,801,587 discloses the use of phentolamine as a vasodilator to treat impotence. U.S. Pat. No. 4,310,535 discloses the use of phentolamine in combination with other drugs for use in the control of immune reactions. The use of phentolamine and clonidine for controlling hypertension is disclosed in U.S. Pat. No. 4,250,191. xcex1-Adrenergic drugs have been found to be useful in the stabilization of intraocular lenses, as disclosed in U.S. Pat. No. 4,443,441. U.S. Pat. No. 4,201,211, discloses the use of a clonidine patch for therapeutic use as a stimulant for the central nervous system.
It is therefore an object of the present invention to provide a topical method of diagnosis for sympathetically maintained pain that has a low incidence of false positives and false negatives.
It is another object of the present invention to provide a topical method of diagnosis and treatment of sympathetically maintained pain that has a low incidence of adverse reactions with relatively minor complications.
Sympathetically maintained pain is treated topically by administering to the site where sympathetically maintained pain is present a sympatholytic agent, such as an xcex1-adrenergic antagonist, xcex11-adrenergic antagonist, xcex12 adrenergic agonist, or other drug that depletes or blocks synthesis of norepinephrine from the sympathetic terminals. Specific chemical formulas of sympatholytic agents are disclosed
Examples demonstrate relief of pain by application of phentolamine or clonidine.
Sympathetic efferent fibers release norepinephrine which in turn activates xcex1-adrenergic receptors. Activation of the xcex1-adrenergic receptors by norepinephrine, either directly or indirectly, excites nociceptors. Activity in the nociceptors then evokes pain and further activity in the sympathetic efferent fibers. This, in turn, results in further discharge of the nociceptors. The goal in therapy is to block the effects of norepinephrine on nociceptors. Topical application to the site where sympathetically maintained pain is present of an xcex1-adrenergic antagonist, xcex11 adrenergic antagonist, xcex12 adrenergic agonist, a combination thereof, or other drug that depletes or blocks synthesis of norepinephrine at the sympathetic terminals (collectively referred to herein as xe2x80x9csympatholytic agentsxe2x80x9d) relieves the pain.
Topical application of the sympatholytic agent is also used in the treatment of peripheral vascular diseases characterized by high alpha-adrenergic tone in cutaneous blood vessels, such as frostbite, Raynaud""s disease, thrombophlebitis, and spastic peripheral vascular disorders.
The compounds used in the present method are known to those skilled in the art. For example, the various classes of compounds and examples thereof are described in The Pharmacological Basis of Therapeutics, 8th Edition, Gill, A. G., T. W. Rall, A. S. Nies, P. Taylor, editors (Pergamon Press, Co., Inc., NY 1990), the teachings of which are incorporated herein.
Several different structural classes of sympatholytic agents have been developed, from which a compound can be selected for use as a topical therapy for sympathetically maintained pain. For example, a class of cyclic amidine compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity, alpha-2 adrenoreceptor agonist activity, or both activities combined may be selected can be represented by Formula I: 
wherein A is selected from aryl, aryloxy, anilino, arylamino, diarylamino, heteroaryl, heteroaryloxy, or heteroarylamino, which may be substituted with one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; B may be independently selected from linear alkylene containing from 1 to 4 methylene units, branched alkylene, imino, or thio; and n is either 2 or 3; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of formula I consists of those compounds wherein A is phenyl, substituted phenyl, phenoxy, substituted phenoxy, naphthyl, tetrahydronaphthyl, or diarylamino; wherein B is methylene or 1-ethylene; and n is 2.
An especially preferred class of compounds of Formula I consists of those compounds wherein A is substituted phenyl, in which positions 2 and 6 of the phenyl ring are substituted by radicals independently selected from hydrido, chloro, methyl, ethyl, cyclopropyl, or thiomethyl, and positions 3, 4, and 5 are substituted by radicals independently selected from hydrido, 2-propyl, tertbutyl; hydroxyl, trifluoromethyl, chloro, or fluoro; and B is methylene, or 1-ethylene when A is substituted phenoxy; and n is 2.
Another especially preferred class of compounds of formula I consists of those compounds wherein A is diarylamino, in which case each aryl group can be independently substituted by hydroxyl; and wherein B is methylene; and n is 2.
Yet another especially preferred class of compounds of Formula-I consists of those compounds wherein A is 1-naphthyl or tetrahydronaphthyl; and B is either zero or one methylene unit; and n is 2.
A family of specifically preferred compounds which are included in Formula I consists of the compounds tetrahydrozoline, naphazoline, phentolamine, dexlofexidine, oxymetazoline, cirazoline, xylometazoline, and tolazidine.
Another class of compounds from which a suitable sympatholytic agent with sympathetic neurotransmitter depleting activity or alpha-1 adrenoreceptor antagonist activity may be selected is that of substituted ureas, represented by Formula II: 
wherein A2 is selected from alkyl, branched alkyl, aryl, aryloxy, heteroaryl, or heterocyclic moiety, which may bear one or more substituents selected from halogen, lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein R1 and R2 may be independently selected from hydrido, lower alkyl, hydroxyl or cyano; wherein R3 and R4 may be independently selected from hydrido or lower alkyl, or together to form a carbonyl moiety; wherein R5 is selected from hydrido or lower alkyl; and wherein n is any value between 0 and 4 inclusive; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula II consists of those compounds wherein A2 is selected from lower alkyl, phenyl, substituted phenyl, phenoxy, substituted phenoxy, anilino, substituted anilino, azacyclic, benzodioxan, and substituted dioxolane; wherein R1 is selected from hydrido, methyl, or hydroxyl, and R2 is selected from hydrido or cyano;. wherein R3 and R3 are independently either hydrido or methyl, or together form a carbonyl; wherein R5 is hydrogen; and n is any value from 0 to 3 inclusive.
An especially preferred class of compounds of Formula II consists of those compounds wherein A2 is selected from lower alkyl, 2,6-dichlorophenyl, phenoxy, (2,6-dichloro)phenoxy, (2,6-dichloro)anilino, -4-phenyl-1,2,3,6-tetrahydropyridinyl, octahydro-1-azocinyl, octahydro-2-azocinyl, benzodioxan-2-yl, or 1,4-dioxaspiro[4,5]dec-2-yl; wherein R1 is selected from hydrido, methyl, or hydroxyl, and R2 is selected from hydrido or cyano; wherein R3 and R3 are independently either hydrido or methyl, or together form a carbonyl; wherein R5 is hydrogen; and n is any value from 0 to 3 inclusive.
A family of specifically preferred compounds of Formula II consists of bethanidine, guanfacine, guanclofine, guanoxan, guanethidine, guanazodine, guanoxyfeh, guandcline, guanoctine, and guanadrel.
Another class of compounds from which a suitable sympatholytic agent may be selected with sympathetic neurotransmitter depleting activity, alpha-1 adrenoreceptor antagonist activity, alpha-2 adrenoreceptor agonist activity, or a combination of these actions, is represented by Formula III: 
wherein A3 is selected from alkyl, branched alkyl, aryl, aryloxy, heteroaryl, or heterocyclic moiety, which may bear one or more substituents selected from halogen, lower alkyl, aryl, alkoxy, hydroxyl, amino, alkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; B2 is either carbon, wherein it forms an unsaturated imino linkage with the adjacent nitrogen, or linear or branched chain alkylene moiety of 1-4 methylene units in length; R1 and R2 are as defined for Formula II; and R6 is selected from hydrogen or lower alkyl, when the attached nitrogen is not incorporated into an unsaturated imino bond; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula III consists of those compounds wherein A3 is selected from phenyl or substituted phenyl; wherein B2 is a carbon attached by a double bond to the adjacent nitrogen to form an imino moiety, or where B2 is a saturated linear alkyl chain of 2 methylene units; and wherein R1, R2, and R6 are hydrogen.
An especially preferred class of compounds of Formula III consists those compounds wherein.A3 is a 2,6-disubstituted phenyl moiety, wherein the substituents are selected from chloro or methyl.
A group of specifically preferred compounds of Formula III consists of guanabenz, guanoxabenz, and guanoclor.
Another class of compounds from which a suitable sympatholytic agent with alpha-2 adrenoreceptor agonist activity may be selected is represented by Formula IV: 
wherein A4 may be selected from aryl, and heteroaryl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; wherein X is selected from thio, imino, or methylene; wherein R7 is selected from hydrogen, lower alkyl, or oxygen-containing heterocycle; and wherein n is either 2 or 3; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula IV consists of those compounds wherein A4 is phenyl; wherein A4 is substituted phenyl, on which positions 2 and 6 of the phenyl ring may be independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl, and positions 3, 4, and 5 may be independently substituted by a radical selected from hydrogen, methyl, trifluoromethyl, fluoro, or cyano; wherein A4 is 3-thienyl, on which positions 2 and 4 are independently substituted by a radical selected from hydrogen, chloro, methyl, ethyl, or cycloalkyl; wherein A4 is 1-naphthyl, 5,6,7,8-tetrahydronaphthyl-1-yl, pyrrolyl, oxazolyl, isoxazolyl, indol-3-yl, indazol-3-yl, quinolinyl, quinazolinyl, quinoxazolinyl, benzoxazolyl, and benzothiophen-3-yl; wherein A4 is pyrimidin-4-yl, on which positions 3 and 5 are independently substituted by hydrogen, chloro, methyl, ethyl, cycloalkyl, or methoxy; wherein R7 is either hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2.
An especially preferred class of compounds of Formula IV consists of compounds wherein A4 is selected from phenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 2,6-diethylphenyl, 3,4-dihydroxyphenyl, 3-fluoro-6-methylphenyl, 2-chloro-5-trifluoromethylphenyl, 2-chloro-4-methylphenyl, 3-chloro-4-methylthien-3-yl, 5,6,7,8-tetrahydronaphth-1-yl, and 4-chloro-5-methoxy-2-methylpyrimidin-4-yl; wherein R7 is hydrogen or tetrahydropyran-2-yl; wherein X is thio or imino; and wherein n is 2.
A specifically preferred class of compounds of Formula IV consists of xylazine, flutonidine, moxonidine, tramazoline, tolonidine, piclonidine, tiamenidine, and clonidine.
Another class of compounds from which a suitable sympatholytic agent with sympathetic neurotransmitter depleting activity alone or in combination with alpha-2 adrenoreceptor agonist activity may be selected is represented by Formula V: 
wherein Y represents the remainder of a cyclic structure selected from 1,2,3,4-tetrahydroisoquinoline or 2,3-dihydroisoindole, which may be substituted by one or more radicals selected from halogen, lower alkyl, alkoxy, hydroxyl, oxo, amino, dialkylamino, aryl, aryloxy, cyano, alkoxycarbonyl, aminocarbonyl, alkylsulfinyl, alkylsulfonyl, alkanoyl, or alkylthio; and wherein R1 and R2 are defined as in Formula II; or a pharmaceutically acceptable salt thereof.
An especially preferred class of compounds of Formula V consists of those compounds wherein Y is substituted tetrahydroisoquinoline, and wherein the preferred substituents are wither hydrogen or halogen, preferably on position 7 of the tetrahydroisoquinoline nucleus, and wherein R1 and R2 are both hydrogen.
A specifically preferred class of compounds of Formula V consists of debrisoquin and guanisoquin.
Another class of compounds from which a suitable sympatholytic agent with alpha-1 antagonist activity may be selected is represented in Formulas VI and VII: 
wherein R8 is hydrogen, alkyl, or cycloalkyl; wherein R9 and R10 are independently selected from hydrogen, alkyl, alkoxy, acyloxy, dialkylamino, or alkylthio; wherein R11 is selected from hydrogen, alkyl, or alkoxy; wherein R12 and R13 are independently selected from hydrogen or alkyl; wherein nxe2x80x2 and nxe2x80x3 independently represent values from 2 to 4 inclusive; and wherein Z may abe selected from alkyl, alkoxy, alkylaryl, alkenylaryl, alkoxyalkyl, hydroxyalkyl, aryl, heteroaryl, and heteroalkyl; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula VI consists of those compounds wherein R8 is hydrogen, R9 and R10 are both alkoxy; wherein R11 is selected from hydrogen or alkoxy; and wherein R12 is selected from hydrogen or alkyl.
A preferred class of compounds of Formula VII consists of those compounds wherein R8 is hydrogen, R9 and R10 are both alkoxy; wherein R11 is selected from hydrogen or alkoxy; and wherein nxe2x80x2 and nxe2x80x3 are independently either 2 or 3.
An especially preferred class of compounds of Formula VI consists of those wherein R9 and R10 are both methoxy; wherein an R11 is selected from hydrogen or methoxy; wherein R12 is selected from hydrogen or methyl; wherein R13 is hydrogen; and wherein Z is selected from ethyl, propyl, butyl, 2-methylpropyl, 1-methoxyethyl, 2-(2-furoyl)-ethenyl, 2-tetrahydrofuranoyl, 2-furoyl, 2-hydroxy-2-methylpropyloxy, 2-hydroxypropyl, and 2-thiomethyl-1,3,4-oxadiozol-4-yl.
An especially preferred class of compounds of Formula VII consists of those compounds wherein R9 and R10 are both methoxy; wherein an R11 is selected from hydrogen or methoxy; wherein Z is selected from ethyl, propyl, butyl, 2-methylpropyl, 1-methoxyethyl, 2-(2-furoyl)-ethenyl, 2-tetrahydrofuranoyl, 2-furoyl, 2-hydroxy-2-methylpropyloxy, 2-hydroxypropyl, and 2-thiomethyl-1,3,4-oxadiazol-4-yl; and wherein nxe2x80x2 is 2 and nxe2x80x3 is 2 or 3.
A specifically preferred class of compounds of Formulas VI and VII consists of alfuzosin, bunazosin, doxazosin, metazosin, neldazosin, prazosin, terazosin, trimazosin, tiodazosin, and MY-5561.
Another class of compounds from which a suitable sympatholytic agent with alpha-1 antagonist activity may be selected is represented in Formula VIII: 
wherein N may be selected from aryl or heteroaryl, which may be substituted with one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, halogen, thioalkyl, dialkylamino, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl or arylsulfonyl; and M can be further defined as: 
wherein R14 and R15 are independently selected from hydrogen, alkyl, alkoxy, or hydroxy; wherein P is selected from heteroaromatic or polycyclic heteroaromatic, which may be substituted by one or more radicals selected from halogen, alkyl, alkoxy, oxo, cyano, alkoxycarbonyl, arylalkyl, trifluromethyl, or aryloxyalkyl; and wherein Q is selected from oxygen or imino; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula VIII consists of those compounds wherein N is phenyl, pyridyl, thienopyridinyl, indolyl, or pyrimidin-2-yl; wherein, if N is phenyl, then the phenyl ring may be substituted by one or more of the following preferred radicals: chloro, methoxy, cyano, thiomethyl, trifluoromethyl; wherein R14 is hydroxy, ethoxy, or methoxy; wherein R15 is hydrogen; and wherein P is selected from 3-pyridyl, 1-naphthyl, 2-quinazolin-1,3-dione, 6,7-methylenedioxyindol-2-yl, 1,3-pyrimidin-2,4-dion-6-yl; 3H-1,2,4-triazol-3-on-2-yl; 1,2,4-triazolo[4,3-a]pyridin-3(2H)-on-2-yl.
An especially preferred class of compounds of Formula VIII consists of those compounds wherein N is selected from phenyl, 3-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3-trifluoromethylphenyl, or 3-indolyl.
A specifically preferred class of compounds of Formula VIII consists of urapidil, solypertine, naftopidil, saterinone, trazodone, nefazodone, tiospirone, SGB-15343-[2-[4-(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4(1H,3H-quinazolinedione monohydrochloride, and IP-661-[2-ethoxy-2-(3xe2x80x2-pyridyl)ethyl]-4-(2xe2x80x2-methoxy-phenyl) piperazine.
Another class of compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity may be selected is represented by Formula IX: 
wherein A5 is selected from aryl, aryloxy, arylalkyloxy, arylamino, cycloalkyl, cycloalkyloxy, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylamino, and heteroarylsulfonyl, which may be substituted by one or more radicals selected from alkyl, branched alkyl, cycloalkyl, hydroxyl, alkoxy, cycloalkylalkyl, alkoxyalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyano, oxo, halogen, thioalkyl, dialkylamino, heterocyclic, arylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, or arylsulfonyl; wherein K is selected from linear alkylene of 0 to 6 methylene units in length, branched alkylene, alkenyl, cycloalkyl, or arylalkyl; wherein R16 and R17 may be independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, arylcarbonyl, arylamino, arylcarbonylamino, arylsulfonylamino, carboxylate, aryloxycarbonyl, or heteroarylcarbonyl; or wherein R16 and R17 together represent a double bond linked to an adjacent substituted carbon; or wherein R16 and R17 represent a spirocyclic ring juncture forming an alicyclic or heterocyclic ring; wherein R18 may be selected from hydrogen, alkyl, alkoxy, aryl, aryloxy, arylamino, or arylcarbonylamino; and wherein Nxe2x80x2xe2x80x3 represents a value of 1 to 3; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula IX consists of those compounds wherein A5 is selected from substituted phenyl, heteroaromatic, or heterocyclic structures; wherein K is a linear alkylene chain of 1 to 4 methylene units in length; wherein R16 is selected from hydrogen, phenyl, substituted phenyl, heteroaromatic, arylcarbonyl, or arylcarbonylamino; wherein R17 is selected from hydrogen or methyl; or wherein R16 and R17 together represent a double bond attached to a substituted carbon, preferably a diaryl substituted carbon; wherein R16 and R17 taken together represent attachment points for a spirocyclic ring moiety, preferably selected from 1,3-dioxalane, or 5,5xe2x80x2-oxazolidin-3-one; and wherein R18 may be selected from hydrogen or arylcarbonylamino.
A specifically preferred class of compounds of Formula IX consists of piperoxan, proroxan, fenspiride, indoramin, and lidanserin.
Another class of compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity is represented by Formula X: 
wherein A6 may be selected from aryl, aryloxy, heteroaryl, heteroaryloxy, arylthio, heteroarylthio, arylalkyl, and heteroarylalkyl, which may be substituted by one or more radicals selected from chloro, hydroxyl, alkoxy, alkyl, amino, aminoalkyl, arylsulfonamino, alkylsulfonamino, aminocarbonyl, aminosulfonyl, thiol, aryl, heteroaryl, or alkylthio; wherein R19, R22, and R23 may be independently selected from hydrogen or alkyl; wherein R20 may be selected from hydrogen or alkyl; wherein R21 may be further described as: 
wherein R24 and R25 may be independently selected from hydrogen or alkyl; wherein A7 is aryl, preferably phenyl or substituted phenyl; and nxe2x80x3xe2x80x3 represents a value of 0 to 4 methylene units. Additionally, Formula X describes compounds wherein R20 and R21 taken together represent contact points which form a ring, such as pyrrolidine or piperidine, which may be further substituted; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula X consists of those compounds wherein A6 is selected from phenyl, substituted phenyl, carbostyril, 2,3-dihydrobenzo[b]thiophen-5-yl, and thiazolyl-2-thio; wherein R19 is hydrogen; wherein R23 is hydrogen or methyl; wherein R20 is hydrogen; wherein R24 and R25 are independently hydrogen or methyl; and wherein A7 is phenyl.
Another preferred class of compounds of Formula X consists of those compounds wherein R20 and R21 together form a piperidine moiety, which is further substituted by a phenylmethyl substituent.
A specifically preferred class of compounds of Formula X consists of labetalol, amosulalol, arotinolol, brefanolol, ifenprodil and tibalosin.
Another class of compounds from which a suitable sympatholytic agent may be selected as an irreversible alpha-1 adrenoreceptor antagonist is represented by Formula XI: 
wherein R26 and R27 are independently selected from alkyl, arylalkyl, aryloxyalkyl, or heteroalkyl; or wherein R26 and R27 taken together represent a ring structure; and wherein G represents a suitable leaving group substituent selected from halogen, alkylsulfonyloxy, or arylsulfonyloxy; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula XI consists of those compounds wherein R26 and R27 are independently taken from phenylalkyl or phenyloxyalkyl, and G is chloro.
A specifically preferred class of compounds of Formula XI consists of phenoxybenzamine and dibenzamine.
Another class of compounds from which a suitable sympatholytic agent may be selected as an alpha-2 adrenoreceptor agonist is represented by Formula XII: 
wherein A8 is selected from aryl or heteroaryl, which may be substituted by one or more radicals independently selected from alkyl, halogen, alkoxy, alkylthio, hydroxyl, amino, arylsulfonylamino, of carboxamido; and wherein R28 is selected from hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.
A preferred class of compounds of Formula XII consists of those compounds wherein A8 is phenyl or substituted phenyl, and R28 is hydrogen or methyl.
A specifically preferred class of compounds of Formula XII consists of detomidine and medetomidine.
A suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity or sympathetic neurotransmitter depleting activity may also be selected from the structural class of compounds known generically as the Rauwolfia alkaloids. As described in Burger""s Medicinal Chemistry, 4th Edition, Part III, pages 302-305 and 932-933 (M. E. Wolff, editor, Wiley-Interscience, New York, 1981), compounds in this class are well known sympatholytic agents. Specifically preferred compounds of this class are reserpine, mediodespidine, deserpidine, rauwulscine, and extracts of Rauwolfia serpentina; or a pharmaceutically acceptable salt thereof.
A suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity may also be selected from the class of compounds known generally as the ergot alkaloids. As described in Burger""s Medicinal Chemistry, 4th Edition, Part III, page 310 (M. E. Wolff, editor, Wiley-Interscience, New York; 1981), compounds of this class are well known sympatholytic agents. Specifically preferred compounds from this class are nicergoline, dihydroergocornine, dihydroergocryptine, dihydroergocristine, amsulosin, BAM-1125, and the mixture of hydrogenated derivatives of the ergotoxine alkaloids.
Another class of compounds from which a suitable sympatholytic agent may be selected as an inhibitor of dopamine beta-hydroxylase is represented by Formula XIII: 
wherein each of R32 through R35 is independently selected from hydrido, alkyl, haloalkyl, mercapto, alkylthio, cyano, alkoxy, alkoxyalkyl and cycloalkyl; wherein J is selected from oxygen atom and sulfur atom; wherein each of R29 and R30 is independently selected from hydrido and alkyl; wherein R31 is selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl,a amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl,
Another preferred class of compounds within Formula XIII consists of those compounds of Formula XIV: 
wherein each of R36, R37 and R40 through R43 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, arylalkyl, aryl, alkoxy, arylalkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl; wherein R36 and R37 together may form oxo or thio; wherein r is a number selected from zero through six, inclusive; wherein each of R38 and R39 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl.
A more preferred class of compounds within Formula XIV consists of those compounds wherein each of R36, R37 and R40 through R43 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through four, inclusive; wherein each of R38 and R39 is independently selected from hydrido, alkyl, amino, monoalkylamino, dialkylamino, phenyl and phenalkyl.
An even more preferred class of compounds within Formula XIV consists of those compounds where in each of R36, R37 and R40 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; wherein r is a number selected from zero through three, inclusive; and wherein each of R38 and R39 is selected from hydrido, alkyl, amino and monoalkylamino. Most preferred are compounds wherein each of R40 through R43 is independently selected from hydrido and alkyl; wherein each of R36 and R37 is hydrido; wherein r is selected from zero, one and two; wherein R38 is selected from hydrido, alkyl and amino; and wherein R39 is selected from hydrido and alkyl. Especially preferred within this class is the compound 5-n-butylpicolinic acid hydrazide (fusaric acid hydrazide).
Another class of compounds from which a suitable sympatholytic agent with dopamine beta-hydroxylase inhibitor activity may be selected to provide the conjugate first residue is represented by Formula XV: 
wherein each of R44 through R48 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, aryloxy, alkoxy, alkylthio, aralkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl, alkynyl, cyanoamino, carboxyl, tetrazolyl, thiocarbamoyl, aminomethyl, alkylsulfanamido, nitro, alkylsulfonyloxy, formoyl and alkoxycarbonyl; with the proviso that at least one of R44 through R48 is 
wherein Axe2x80x2 is xe2x80x94Coxe2x80x94R49 or xe2x80x94NR51R52 wherein R49 is selected from hydrido, alkyl, hydroxy, alkoxy, alkylthio, phenyl, phenoxy, benzyl, benzyloxy, xe2x80x94OR50 and xe2x80x94NR53R54, wherein R50 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and benzyl; wherein each of R51 through R54 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkanoyl, alkoxycarbonyl, carboxyl, amino, cyanoamino, monoalkylamino, dialkylamino, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; wherein t is a number selected from zero through four, inclusive; or a pharmaceutically-acceptable salt thereof.
A preferred family of compounds within Formula XV consists of those compounds characterized as chelating-type inhibitors of Formula XVI: 
wherein each of R49 through R52 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, phenyl, benzyl, alkoxy, phenoxy, benzyloxy, alkoxyalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, amido, alkylamido, hydroxyamino, carboxyl, carboxyalkyl, alkanoyl, cyanoamino, carboxyl, thiocarbamoyl, aminomethyl, nitro, formoyl, formyl and alkoxycarbonyl; and wherein R53 is selected from hydrido, alkyl, phenyl and benzyl.
A class of specifically-preferred compounds of Formula XVI consists of:
5-n-butylpicolinic acid (fusaric acid);
5-n-butylpicolinic acid (fusaric acid);
picolinic acid;
5-nitropicolinic acid;
5-aminopicolinic acid;
5-N-acetylaminopicolinic acid;
5-N-propionylaminopicolinic acid;
5-N-hydroxyaminopicolinic acid;
5-iodopicolinic acid;
5-bromopicolinic acid;
5-chloropicolinic acid;
5-hydroxypicolinic acid;
5-methoxypicolinic acid;
5-N-propoxypicolinic acid;
5-N-butoxypicolinic acid;
5-cyanopicolinic acid;
5-carboxylpicolinic acid;
5-n-butyl-4-nitropicolinic acid;
5-n-butyl-4-methoxypicolinic acid;
5-n-butyl-4-ethoxypicolinic acid;
5-n-butyl-4-aminopicolinic acid;
5-n-butyl-4-hydroxyaminopicolinic acid; and
5-n-butyl-4-methylpicolinic acid.
Especially preferred of the foregoing class of compounds of Formula XVI is the compound 5-n-butylpicolinic acid (fusaric acid).
Another class of compounds from which a suitable sympatholytic agent with dopamine beta-hydroxylase inhibiting activity is represented by Formula XVII: 
wherein R55 is hydrido, hydroxy, alkyl, amino and.alkoxy; wherein R56 is selected from hydrido, hydroxy and alkyl; wherein each of R57 and R59 is independently selected from hydrido, alkyl and phenalkyl; wherein R59 is selected from hydrido and R60Cxe2x80x94 with R60 selected from alkyl, phenyl and phenalkyl; wherein u is a number from one to three, inclusive; and wherein v is a number from zero to two, inclusive; or a pharmaceutically-acceptable salt thereof.
A preferred class of compounds within Formula XVII consists of those compounds wherein R55 is selected from hydroxy and lower alkoxy; wherein R56 is hydrido; wherein R57 is selected from hydrido and lower alkyl; wherein R58 is hydrido; wherein R59 is selected from hydrido and R60Cxe2x80x94 with R60 selected from lower alkyl and phenyl; wherein u is two; and wherein v is a number from zero to two, inclusive.
A more preferred class of compounds within Formula XVII consists of those compounds of Formula XVIII 
wherein R61 is selected from hydroxy and lower alkyl;
wherein R57 is selected from hydrido and lower alkyl;
wherein R59 is selected from hydrido and R60Cxe2x80x94 with R60 selected from lower alkyl and phenyl and v is a number from zero to two, inclusive.
A more preferred class of compounds within Formula XVIII consists of those compounds wherein R61 is hydroxy; wherein R57 is hydrido or methyl; wherein R59 is hydrido or acetyl; and wherein n is a number from zero to two, inclusive.
Most preferred within the class of compounds of Formula XVIII are the compounds 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline and 1-(2-mercaptacetyl)-L-proline (also known as captopril.)
Specifically preferred sympatholytic compounds which are not encompassed in Formulas I through XVIII from which a suitable agent may be selected include the sympathetic neurotransmitter depleting agents bretylium and MJ-10459, and the alpha-1 adrenergic antagonist methylapogalanthamine.
xcex1-Adrenergic blocking agents bind selectively to the a class of adrenergic receptors and thereby interfere with the capacity of sympathomimetic amines to initiate actions at these sites. xcex1-Adrenergic blockade is due to the direct action of these drugs on a receptors and is independent of any effects on adrenergic neurons or on the basic response mechanisms of effector cells. xcex2-Adrenergic receptors are not affected by conventional doses of any xcex1-blocking agent currently in use.
Examples of xcex1-adrenergic antagonists include phenoxybenzamine, dibenzamine, phentolamine, tolazoline, and prazosin. Phenoxybenzamine and dibenzamine bind covalently to the a receptor and produce an irreversible type of blockade. Phentolamine, tolazoline, and prazosin bind reversibly and antagonize the actions of sympathomimetic amines competitively. There are differences in the relative abilities of xcex1-adrenergic blocking agents to antagonize the effects of sympathomimetic amines at the two subtypes of a receptors, xcex11 and xcex12 receptors. Phenoxybenzamine is approximately 100-fold more potent in blocking xcex11 (postsynaptic) receptors than xcex12 receptors (that modulate neural release of transmitter). Prazosin is also a highly selective xcex11-blocking agent, while phentolamine is only three to five times more potent in inhibiting xcex11-than xcex12-adrenergic receptors. In contrast, yohimbine is a selective xcex12 blocker and has been shown to prevent the antihypertensive effect of systemic clonidine. Phentolamine is the preferred xcex1-adrenergic antagonist at this time.
These compounds have previously been administered systemically, either orally or by injection. Systemic administration requires high doses and thus systemic side effects (e.g., postural hypotension, tachycardia, nasal stuffiness, headache) limit their usefulness. In the method described herein, the compounds are administered topically, in a suitable pharmaceutical carrier, many of which are known to those skilled in the art. The carrier can be in the form of a lotion, ointment, solution, or transdermal patch. Topical administration also includes iontophoresis wherein an electric current drives the drug, in the form of an ion such as a pharmaceutically acceptable salt, into the skin. The topical application allows the drug to reach high concentration at the desired target without appreciable systemic dosing. Thus the many of the side effects of these compounds, observed following systemic administration, are avoided by topical administration.
Another drug class, xcex12-agonists, the preferred example being clonidine, an antihypertensive agent stimulating both central and peripheral xcex11- and xcex12-adrenergic receptors, also antagonize the effects of norepinephrine. This is because sympathetic terminals possess xcex12-receptors which when activated block the release of norepinephrine. Thus the xcex12-agonists such as clonidine antagonize xcex11-receptors indirectly by preventing the release of norepinephrine.
A third class of effective drugs are those that deplete norepinephrine from the sympathetic terminals. The prototype drug in this class is guanethidine. Other examples are bretyliut, bethanidine, debrisoquin, and reserpine.
Additional compounds are specific inhibitors of catecholamine synthesis and monoamine oxidase inhibitors.
These compounds are normally administered systemically (orally or by intravenous injection), although as described herein they are administered in a pharmaceutically acceptable topical carrier or by iontophoresis, as described above.
The effective dosage of these compounds is determined by applying dosages of the compound to the affected site and observing local vasodilatation. Vasodilatation can be determined by laser Doppler flow measurements or by measuring local increases in skin temperature.